1,2,3-benzotriazin-4(3h)-ones

ABSTRACT

Disclosed are compounds of the class of 1,2,3-benzotriazin4(3H)-ones which are substituted at the 3- position and which are substituted at at least two of the 6,7 and 8- positions by alkoxy or by an adjacent methylenedioxy, e.g. 6,7-dimethoxy-3-(3morpholinopropylamino)-1,2,3-benzotriazin-4(3H)-one. The compounds have pharmacological activity in animals, e.g. antiinflammatory activity. The compounds may be prepared, for example, by alkylation of the corresponding 3-unsubstituted compounds and by reaction of an appropriately disubstituted anthranil amide with sodium nitrite and a strong inorganic acid, e.g. sulfuric acid.

United States Patent [191 Kathawala June 18, 1974 [22] Filed:

l l ,2,3-BENZOTRIAZIN-4( 3H )-ONES [75] Inventor: Faizulla G. Kathawala,West Orange, NJ.

Related US. Application Data [63] Continuation of Ser. No. 124,486,March 15, 1971,

abandoned.

52 us. (1.... 260/2471 A, 260/240 AS, 424/249,

424/248 51 lm. cu com 55/08 581 Field of Search 260/248 AS, 247.7 A

[56] References Cited UNITED STATES PATENTS 3,163,646 12/1964 Herlingeret al 260/248 X 3,316,262 4/1967 Hasspacher et al 260/248 PrimaryExaminer-John M. Ford Attorney, Agent, or Firm-Gerald D. SharkinABSTRACT Disclosed are compounds of the class of1,2,3-benzotriazin-4(3H)-ones which are substituted atthe 3- positionand which are substituted at at least two of the 6,7 and 8- positions byalkoxy or by an adjacent methylenedioxy, e. g. 6,7-dimethoxy .3-( 3-morpholinopropylamino l ,2,3-ben2 otriazin- 4(3H)-one. The compoundshave pharmacological activity in animals, e.g. anti-inflammatoryactivity. The compounds may be prepared, for example, by alkylation ofthe corresponding 3-unsubstituted compounds and by reaction of anappropriately disubstituted anthranil amide with sodium nitrite and astrong inorganic acid, e.g. sulfuric acid.

17 Claims, N0 Drawings The compounds of the present invention may berepresented by the structural formula I:

wherein R is lower alkyl of 1 to 6 carbon atoms,

each R' is lower alkyl of l to 3 carbon atoms or both R together withthe nitrogen to which they are attached form X is oxygen, (CH or m is to2,

R is lower alkyl of 1 to 3 carbonatoms,

n is 0 to 3, provided that both R are not lower alkyl when n is 0, and

each of Y, Y" and Y" is hydrogen or lower alkoxy of l to 3 carbon atomsprovided at least two of Y, Y and Y" are lower alkoxy, or two of Y Y andY which are adjacent to each other together form methylenedioxy (whilethe other is hydrogen).

The compounds of the formula I may be prepared by reacting a compound ofthe formula ll:

| N H Y C g II wherein Y, Y and Y" are as above defined, with a compoundof the formula 11]:

wherein R is as defined and Z is halo of atomic weight of from 35 to 127or -OB in which B is methane sulfonyl, benzene sulfonyl orp-toluenesulfonyl, in the presence of a base.

The preparation of compounds I by'reacting a compound II with a compoundIII is suitably carried out at temperatures in the range of from 30C. toC., typically 40C. to 80C., and in the presence of strong base such assodium hydride, sodium hydroxide and the like. The reaction isconveniently carried out in the presence of an inert'organic solvent ofconventional type, such as a lower alkanol, e.g. methanol or ethanol, ordimethylacetamide. The reaction product of the formula 1 may be isolatedfrom the resulting reaction mixture by working up by conventionalprocedures.

The compounds of the formula 1 may be also prepared by reacting acompound of the-formula 1V in which R, Y, Y and Y are as above defined,with a diazotisation reagent in the presence of a strong acid.

The preparation of compounds I from compounds 1V is suitably carried outat temperatures in the range of from minus 30C. to plus 20C., typicallyminus 10C. to plu's.10C. The diazotisation reagent is desirably sodiumnitrite and the acid employed is most suitably sulfuric acid. Thereaction is of known type and the resulting reaction product of theformula 1 may be isolated from the resulting reaction mixture by workingup by established procedures.

The compounds of the formula ll are preferably prepared from compound 1Vin which R is hydrogen by the procedure above-described for thepreparation of compounds I from compounds IV. The compounds of theformula IV in which R is hydrogen may themselves be prepared inaccordance with the following reaction 1 2 1 YI/ Y]! Y, Hydrazine yo-oorn step A Y G-NHNH1 V v VI Rana Nickel step fi ln Ethanol Y I NH, YC-NH:

IVB

in which Y, Y and Y" are as above defined.

The reaction of Step A is of known type and suitably effected atelevated temperatures in the range of 50C.

.to 150C., preferably 80C. to 130C. While inert organic solvents ofconventional type may be employed it is generally preferred to employ anexcess of hydrazine of the solvent for the reaction.

such as ethanol or methanol.

The intermediates of the formula IV in general may be prepared accordingto the following process:

in which R is as above defined.

The process of Step C involving the reaction of a compound Vll with anamine of the formula Vlll may be effected at temperature in the range ofC. to l20C., preferably 50C. to 100C. The reaction is desirably carriedout in the presence of an inert organic solvent which may be any ofseveral of conventional type, preferably a lower alkanol such asmethanol or ethanol. When producing compounds IV in which-R is hydrogenthe compound VIII is ammonia and the solvent system desirably includesor consists of water such that aqueous ammonium hydroxide is preferablyemployed as the source of both ammonia and solvent. In such cases thereaction is generally carried out at temperatures of from 0C. to 60C.,preferably C. to 25C.

The compounds of the formula V and the formula Vll are either known ormay be prepared by procedures well established for preparation of theknown compounds.

-The compounds of the formula I in which R constitutes a basic sidechain, e.g. R is dialkylaminoalkyl, morpholino and the like, form acidaddition salts and those compounds of the formula I in the form ofnontoxic pharmaceutically acceptable salts are included within the scopeof the present invention. Such phar maceutically acceptable saltsinclude, by way of illustration, the hydrochloride, fumarate,maleate,.formate, acetate, sulfonate and malonate. The acid additionsalts of the subject compound 1 may be produced from thecorresponding'free bases by conventional procedures known in theart-Conversely, the free basis may be produced from the acid additionsalts by conventional procedures.

The compounds of formula I are useful because the possesspharmacological activity in animals. In particular, the compounds 1 areuseful as anti-inflammatory agents as indicated by an inhibition ofCarrageenan induced edema in rats and a reduction in foot volume and animprovement in grip strength in the adjuvant arthritis test in ratsusing Mycobacteria butyricum in Freunds adjuvant. For such use, thecompounds may be combined with a pharmaceutically acceptable carrier,and such other conventional adjuvants as may be necessary, andadministered orally in such forms as tablets, capsules, elixirs,suspensions and the like or parenterally in the form of an injectablesolution or suspension. The dosage administered will, of course, varydepending upon the compound used and the mode of administration.However, in general, satisfactory results are obtained when administeredat a daily dosage of kilogram of body weight, preferably given individed doses 2 to 4 times a day, or in sustained release form. For mostmammals the administration of from about 120 milligrams to about 2000milligrams of the compound per day provides satisfactory results anddosage forms suitable for internal administration comprise from about 30milligrams to about 1000 milligrams of the compound in admixture with asolid or liquid pharmaceutical carrier or diluent.

For the above usage, oral administration with carriers may take place insuch conventional forms as tablets, dispersible powders, granules,capsules, syrups and elixirs. Such compositions may be preparedaccording to any method known in the art for the manufacture ofpharmaceutical compositions, and such compositions may contain one ormore conventional adjuvants, such as sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide anelegant and palatable preparation. Tablets may contain the activeingredient in admixture with conventional pharmaceutical excipients,e.g. inert diluents such as calcium carbonate, sodium carbonate, lactoseand talc, granulating and disintegrating agents, e.g., starch andalginic acid, binding agents, e.g., starch, gelatin and acacia, andlubricating agents, e.g., magnesium stearate, stearic acid and tale. Thetablets may be uncoated or coated by known techniques to delaydisintegration and adsorption in the gastro-intestinal tract and therebyprovide a sustained action over a longer period. Similarly, suspensions,syrups and elixirs may contain the active ingredient in admixture withany of the conventional excipients utilized for the preparation of suchcompositions, e.g., suspending agents (methylcellulose, tragacanth andsodium alginate), wetting agents (lecithin, polyoxyethylene stearate andpolyoxyethylen'e sorbitan monooleate) and preservatives(ethyl-phydroxybenzoate). Capsules may contain the active ingredientalone or admixed with an inert solid diluent, e.g., calcium carbonate,calciumphosphate and kaolin. The preferred pharmaceutical compositionsfrom the standpoint of preparation and ease of administration are solidcompositions, particularly hard-filled capsules and tablets.

A representative formulation is a tablet which may be administered fourtimes a day and prepared by conventional tabletting techniques tocontain the following ingredients:

Ingredient Weight (mg.)

Compound of the formula 1 Tragacanth l0 Lactose 147.5 Corn Starch 25Talcum l5 Magnesium stearate 2.5

EXAMPLE 1 6,7-Dimethoxyl ,2,3-benzotriazin-4( 3l-l)-o ne.

CHaO

onto \C/ l STEP A: Preparation of 4,5 -dimethoxy-anthranilic acidhydrazide.

A mixture of 50 g. of 4,5-dimethoxymethylanthranilate and 200 ml. ofanhydrous hydrazine is refluxed for l 30 minutes, and thenpoured ontoice-water. The resulting mixture containing a grey-white precipitate isfiltered and the recovered precipitate washed first with ice-cold water,then with diethyl ether and then dried overnight under high vaccum at70C. to obtain 4,5- dimethoxy-anthranilic acid hydrazide, m.p. l76-l77C.

STEP B: Preparation of 4,5-dimethoxy-anthranilamide.

To a suspension of prepared by heating together 4.0

g. of 4,5-dimethoxy-anthranilamide in 60 ml. of npropanol and 20 ml. of3N sulfuric acid and then cooling to 05C. is added dropwise overone-half hour 1.5 g. of sodium nitrite in 7.0 ml. of water. Theresulting mixture is kept at 05C. for 3 hours and then allowed to standovernight at room temperature. The mixture is then diluted with waterwhile stirred vigorously and then filtered to recover the precipitatesolids which are washed with water, redissolved in 1.5 liters of boilingchloroform/ethanol H) which is filtered while hot. The filtrate isconcentrated in vacuo to obtain 6,7 dimethoxy-l,2,3-benzotriazin-4(3H)-one, mp. 273-274C.

EXAMPLE 2 3-(B-N-homopiperidino)ethyl-6,7-dimethoxy-1,2,3-benzotriazin-4( 3H )-one. I

'dimethoxyl ,2,3,-benzotriazin-4( 3H )-one,

EXAMPLE 3 Following the procedure of Example 1, the following compoundis prepared:

a 6,7-methylenedioxy-1 ,2,3-benzotriazinmp. 250-251C.

EXAMPLE 4 Following the procedure of Examples 1 and 2, the

following compounds of the invention are preparedi a.3-B-dimethylaminoethyl-6,7-dimethoxy-l ,2,3-benzotriazin-4(3H)-one, mp.165-167C.

b. 3-methyl-6,7-dimethoxy.- l ,2,3-benzotriazin- 4(3H)-one, m.p.26l-262C.

c. 3-isopropyl-6,7-dimethoxyl ,2,3-benzotriazin- 4(3l-l)-one, mp.250-251C.

d. 3-ethyl-6,7-dimethoxy-l ,2,3-benzotriazin- 4(3H)-one, mp. 217-218C.

e. 3-isopropyl-6,7,8-trimethoxy-l ,2,3-benzotriazin- 4(3H)-one, m.p.IOU-102C. (crystallized from diethyl ether).

f. 3-B-dimethylaminoethyl-6,7,8-trimethoxy-l ,2,3-benzotriazin-4(3l-l)-one, m.p. 92C. (crystallized from diethyl ether).

g. 3-(2-hydroxyethyl)-6,7-dimethoxy-l ,2,3-benzotriazin-4(3H)-oneacetate, m.p. l75-l77C. (crystallized from ethyl acetate).

EXAMPLE 5 3-( 3-morpholinopropyl )-6,7-dimethoxyl ,2,3-benzotriazin-4(3H )-one N-CHPCm-GHPN 0 STEP A: Preparation ofN-(3-morpholinopropyl)-4,5- dimethoxyanthranilamide.

A suspension of 11.2 g. of 6,7-dimethoxyisatoic anhydride and 8.9 g. ofN-(3-aminopropyl)-morpholine in 250 ml. of ethanol is refluxed for 15minutes'and the resulting solution cooled and evaporated in vacuo. Theresulting oil is dissolved in methylene chloride and treated first witha 10% aqueous sodium bicarbonate solution and then with water. Theresulting solution is dried and evaporated in vacuo to obtain an oil ofN-( 3- morpholinopropyl)-4,5-dimethoxyanthranilamide. STEP B:Preparation of 3-(3-morpholinopropyl)-6,7- dimethoxy-l,2,3-benzotriazin-4( 3H )-one.

To a suspension of 15.] g. morpholinopropyl)-4,5-dimethoxyanthranilamidein ml. of n-propanol and 47 ml. of 3N. sulfuric acid at 05C. is added3.9 g. of sodium nitrite in 22 ml. of water. The resulting mixture isstirred at ice-bath temperature for a few hours (about 6 hours) and thenat room temperature for 24 hours. The resulting mixture is treated with2N sodium hydroxide solution and diluted with ice water and then withmethanol. The re sulting mixture is extracted with methylene chloride,the extract dried over sodium sulfate and treated with ethanol tocrystallize 3-(3-morpholinopropyl)-6,7-

m.p. l6ll63C.

of N- a EXAMPLE 6 wherein R is lower alkyl,

each R is lower alkyl or both R together with the nitrogen to which theyare attached form X is oxygen, -(CH or provided at least two of Y, Y andY" are lower alkoxy, or two of Y, Y and Y which. are adjacent to eachother together form methylenedioxy;

or a pharmaceutically acceptable non-toxic acid addition salt thereof.

2. A compound of claim 1 in which R is lower alkyl.

3. A compound of claim 2 in which Y and Y are methoxy and Y" is hydrogen4. The compound of claim 3 in which R is methyl.

5. The compound of claim 3 in which R is isopropyl.

6. The compound of claim 3 in which R is ethyl.

7. The compound of claim 2 in which R is isopropyl and each Y, Y and Yis methoxy.

8. A compound of claim 1 in which R is fl-dimethylaminoethyl.

9. The compound of claim 8 in which Y and Y are methoxy and Y ishydrogen.

10. The compound of claim 8 in which each of Y, Y and Y is methoxy.

11. A compound of claim 1 in which R is (CH -NRR.

12. A compound of claim 11 in which R is B-(N- homopiperidino) ethyl.

13. The compound of claim 12in which Y and Y are methoxy and Y ishydrogen.

14. A compound of claim 11 in which R is 3- morpholinopropyl.

15. The compound of claim 14 in which Y and Y are methoxy and Y" ishydrogen.

16. A compound of claim 1 in which R is l7.- The compound of claim 16 inwhich R" is methyl, Y and Y are methoxy and Y is hydrogen.

2. A compound of claim 1 in which R is lower alkyl.
 3. A compound ofclaim 2 in which Y and Y'' are methoxy and Y'''' is hydrogen.
 4. Thecompound of claim 3 in which R is methyl.
 5. The compound of claim 3 inwhich R is isopropyl.
 6. The compound of claim 3 in which R is ethyl. 7.The compound of claim 2 in which R is isopropyl and each Y, Y'' andY'''' is methoxy.
 8. A compound of claim 1 in which R is Beta-dimethylaminoethyl.
 9. The compound of claim 8 in which Y and Y'' aremethoxy and Y'''' is hydrogen.
 10. The compound of claim 8 in which eachof Y, Y'' and Y'''' is methoxy.
 11. A compound of claim 1 in which R is-(CH2-)n-NR''R''''.
 12. A compound of claim 11 in which R is Beta-(N-homopiperidino) ethyl.
 13. The compound of claim 12 in which Y andY'' are methoxy and Y'''' is hydrogen.
 14. A compound of claim 11 inwhich R is 3-morpholinopropyl.
 15. The compound of claim 14 in which Yand Y'' are methoxy and Y'''' is hydrogen.
 16. A compound of claim 1 inwhich R is
 17. The compound of claim 16 in which R'''' is methyl, Y andY'' are methoxy and Y'''' is hydrogen.